Patisiran exposure in early pregnancy: a case report

We describe here the first case of exposure to patisiran treatment, a small interfering RNA molecule, during early pregnancy of a 36-year-old woman with symptomatic hereditary transthyretin-related amyloidosis. There were no major complications during pregnancy and delivery, except for a postpartum hemorrhage due to uterine atony. Vitamin A levels had to be closely monitored during pregnancy, and vitamin A substitution adapted accordingly. There was no sign of minor or major congenital abnormalities of the baby. One month after delivery, the patient showed slight clinical and electrophysiological signs of neuropathy progression due to patisiran treatment withdrawal. Patisiran infusions were resumed 3 months after delivery. Due to the unknown teratogenic potential of patisiran, the risk of neuropathy worsening associated with withholding treatment must of course be weighed against a potential teratogenic risk of treatment during pregnancy. Vitamin A levels need to be closely assessed, and substitution must be adapted accordingly, to avoid embryofetal adverse outcome due to vitamin A deficiency or toxicity.

In December 2022, the patient informed us of an unplanned pregnancy (she already had three healthy children).Despite information on the uncertainties on the risks for the pregnancy due to patisiran treatment, 1 low levels of prealbumin and vitamin A, the patient and her husband decided to continue with the pregnancy.She thus received the last dose of patisiran during the third week of amenorrhea (last dose given before the patient informed us of the pregnancy), and treatment was then discontinued.A close follow-up with a maternofetal medicine specialist was planned, including monthly dosage of serum vitamin A and prealbumin, and fetal ultrasound follow-up at 13,  17, 22, 31, and 34 weeks of gestation.Vitamin A substitution was increased at 4000 IU per day at the beginning of pregnancy given the uncertainty on available circulating vitamin A (low levels of

TherapeuTic advances in neurological disorders
Volume 17 serum vitamin A) (Table 1).Substitution was discontinued at 3 months of gestation, when vitamin A levels were within normal ranges.There was a progressive increase in prealbumin (TTR) levels over months (Table 1).The pregnancy was harmonious with a good fetal growth.No fetal malformations were detected.After a spontaneous labor, the patient delivered a healthy male infant at 40 weeks of gestation with an APGAR score at 9/9/9, birth weight 3540 g, length 49 cm, and a normal cranial perimeter at 34 cm.His clinical exam at day 2 was normal, including his neurological exam.Delivery was complicated with a postpartum hemorrhage of 1400 mL, due to uterine atony, treated with sulprostone then a Bakri balloon and tranexamic acid perfusions.A postpartum anemia at 84 g/L was treated with iron infusion.There was no sign of minor or major congenital abnormalities.

Discussion
We present here the first case of exposure to patisiran in early pregnancy.As for most pharmacological treatments, pregnant women have been excluded from clinical studies assessing patisiran effectiveness and safety.In the APOLLO and in the global open label extension studies, women of childbearing age must have a negative pregnancy test and use two  highly effective methods of contraception before inclusion. 2,3A patisiran pregnancy exposure registry is currently ongoing (ALN-TTR02-010, NCT05040373), sponsored by Alnylam Pharmaceuticals.Women exposed to patisiran treatment at any point of the pregnancy can be enrolled in the registry, with contact information listed on the Food and Drug Administration website. 4 this case report, the exposure to patisiran has been limited to early pregnancy but without a clear definition on up to when exactly.While the last injection took place during the third week after the last menstruation period, pharmacokinetic studies show a very flat steady-state concentration curve suggesting that exposure may have persisted beyond the classical seven times the 3-day half-life of patisiran (usually, a full drug wash-out is expected after seven half-lives).This is the reason why the potential impact of patisiran treatment during organogenesis was raised by the interprofessional team specialized in the management of pregnancies complicated by chronic neurological diseases, who thus closely monitored this high-risk pregnancy.
Currently, there are no reported human exposures to patisiran during pregnancy.Animal data suggest no risk at human therapeutic doses, but not at toxic doses to humans in rodents and rabbits. 5The high molecular weight of patisiran (i.e.14,304 daltons) and the properties of its lipid nanoparticles coating (large size, polyethylene glycol content) make placental transfer unlikely, unless it has a specific transfer mechanism. 6,7The lipid nanoparticle coating, the same as the one used in mRNA CoVID-19 vaccines, is known to induce some level of systemic inflammation. 8It is unknown whether this immunogenicity may induce pregnancy or neonatal adverse events.However, women vaccinated during pregnancy with mRNA CoVID-19 vaccine did not experience higher adverse pregnancy or neonatal outcomes in recent studies, suggesting a reasonable safety profile of lipid nanoparticles coating. 9,10In the absence of human reproductive safety information, the Swiss summary of product characteristics states that pregnancy should be excluded before starting treatment with patisiran, and women of childbearing age should use effective contraception.In women planning a pregnancy, patisiran and vitamin A supplementation should be discontinued, and serum vitamin A levels should be monitored and been returned to normal before conception is attempted.The child's psychomotor development should then be monitored according to local pediatric recommendations.
Vitamin A imbalances linked to the mechanism of action of patisiran itself, or to the need for vitamin A substitution during its use, could affect the outcome of pregnancy.TTR protein, targeted by patisiran, is directly involved in the transport of vitamin A (retinol) in association with retinol-binding protein.Following patisiran treatment, serum vitamin A levels decreases, with a mean reduction over 18 months of 62.4%. 11Therefore, to avoid ocular toxicity due to a vitamin A deficiency (VAD), a substitution with vitamin A is mandatory, at a dose of 2500 IU/day according to Swiss recommendations.Vitamin A is a crucial micronutrient for the fetus and exerts systemic effects on several fetal organs and skeleton.VAD, particularly in the third trimester of pregnancy, has been shown to be associated with an increased risk of preterm delivery, maternal anemia and infections, low birth weight, and overall newborn mortality and morbidity. 12,13n the other hand, high vitamin A intake, especially in the first trimester of pregnancy, can be teratogenic. 14Therefore, in pregnant women exposed to patisiran, serum vitamin A levels must be closely monitored, and vitamin A substitution adapted accordingly.According to the World Health Organization, vitamin A substitution of pregnant women should not exceed 10,000 IU daily or 25,000 IU weekly, to avoid teratogenicity. 15In our patient, vitamin A levels remained relatively low during the first trimester of pregnancy, before being corrected by a more intensive vitamin substitution.
The patient's delivery was complicated by postpartum hemorrhage due to uterine atony.There seems to be no causal relationship between this complication and patisiran.Indeed, patisiran treatment is not associated with hemorrhagic complications or the occurrence of coagulation disorders, and VAD seems not to be associated with an increased risk of uterine atony. 16e uncertainties on the risks for the pregnancy need to be weighed against the risk of neuropathy worsening associated with withholding treatment during the pregnancy, pending further studies.In the literature, untreated hATTR patients have shown variable rates of neuropathy progression.
In the Conceição et al. 17

study, most of untreated
hATTR patients with a p.Val50Met mutation showed signs of clinical and electrophysiological neuropathy worsening during follow-ups, as early as 12 months.In our patient, stopping patisiran treatment during pregnancy and breastfeeding (11 months in total), was probably associated with a slight progression of the neuropathy, as evidenced by an accentuation of pre-existing sensory and autonomic symptoms and a mild decrease in amplitude of lower limbs motor and sensory nerve action potential (SNAP) in NCS, with however stable ESC and functional and disease severity clinical scores.Yet, those variations in NCS values could be related to an interexaminer variability and do not reach the threshold of a significant worsening, defined as a >50% decrease in amplitude of the motor and/or sensory sum score. 18

Conclusion
Due to the unknown teratogenic potential of patisiran, the risk of neuropathy worsening associated with withholding treatment must of course be weighed against a potential teratogenic risk of treatment during pregnancy, pending further studies.Vitamin A levels need to be closely assessed, and substitution must be adapted accordingly, to avoid embryofetal adverse outcome due to VAD or toxicity.Women exposed to patisiran treatment at any point of the pregnancy can be enrolled in the currently ongoing exposure registry.

Table 1 .
Serum vitamin A and prealbumin (TTR) levels during pregnancy.

Table 2 .
Functional and severity scores, ESC, and NCS parameters pre-and post-pregnancy.